The invention relates to a novel polyamino acid-catalyzed process for the enantioselective epoxidation of xcex1,xcex2-unsaturated enones and xcex1,xcex2-unsaturated sulfones in the presence of specific cocatalysts.
Chiral, nonracemic epoxides are known as valuable synthons for preparing optically active drugs and materials (for example, (a) Bioorg. Med. Chem., 1999, 7, 2145-2156; and (b) Tetrahedron Lett., 1999, 40, 5421-5424). These epoxides can be prepared by enantioselective epoxidation of double bonds. In this case, two stereocenters are produced in one synthetic step. It is therefore not surprising that a large number of methods have been developed for the enantioselective epoxidation of double bonds. However, there is still a great need for novel, improved methods for enantioselective epoxidation.
The epoxidation methods limited to the specific substrates in each case include methods for the enantioselective epoxidation of xcex1,xcex2-unsaturated enones.
Thus, for example, the use of chiral, nonracemic alkaloid-based phase-transfer catalysts for the epoxidation of enones is described in Tetrahedron Lett., 1998, 39, 7563-7566, Tetrahedron Lett., 1998, 39, 1599-1602, and Tetrahedron Lett., 1976, 21, 1831-1834.
Tetrahedron Lett., 1998, 39, 7353-7356, Tetrahedron Lett., 1998, 39, 7321-7322, and Angew. Chem., Int. Ed. Engl., 1997, 36, 410-412 furthermore describe possibilities for the metal-catalyzed asymmetric epoxidation of enones using organic hydroperoxides.
WO-A 99/52886 describes the possibility of enantioselective epoxidation of enones in the presence of catalysts based on sugars.
Another method for epoxidation using Zn organyls and oxygen in the presence of an ephedrine derivative has been published in Liebigs Ann./Recueil, 1997, 1101-1113.
Angew. Chem., Int. Ed. Engl., 1980, 19, 929-930, Tetrahedron, 1984, 40, 5207-5211, and J. Chem. Soc., Perkin Trans. 1, 1982, 1317-24 describe the Julixc3xa1 epoxidation method in which enantiomer- and diastereomer-enriched polyamino acids are able, in the presence of aqueous hydrogen peroxide and NaOH solution and of an aromatic or halogenated hydrocarbon as solvent, to catalyze the enantioselective epoxidation of xcex1,xcex2-unsaturated enones. Further developments of these so-called three-phase conditions are to be found in Org. Synth.; Mod. Trends, Proc. IUPAC Symp. 6th., 1986, 275. The method is now generally referred to as the Julixc3xa1-Colonna epoxidation.
According to EP-A 403,252, it is possible also to employ aliphatic hydrocarbons advantageously in this Julixc3xa1-Colonna epoxidation in place of the original solvents.
WO-A 96/33183 describes as a specific embodiment the possibility of carrying out the enantioselective epoxidation of enones also in the presence of the phase-transfer catalyst Aliquat(copyright) 336 ([(CH3)(C8H17)3N+]Clxe2x88x92) if at the same time a polyamino acid, an organic solvent (such as, for example, dichloromethane), sodium perborate (which is of low solubility in water) as oxidant, and alkali (for example, NaOH) are present.
Despite these improvements, the three-phase conditions have distinct disadvantages. The reaction times under the original conditions are in the region of days even for reactive substrates. For example, 1 to 6 days are required for the epoxidation of trans-chalcone, depending on the polyamino acid used (Tetrahedron, 1984, 40, 5207-5211). A preactivation of the polyamino acid carried out in the reaction vessel, by stirring in the solvent with the addition of NaOH solution for 12 to 48 h, shortens the reaction time for many substrates to 1 to 3 days. In this case, no intermediate workup of the catalyst is necessary (EP-A 403,252). The preactivation can be reduced to a minimum of 6 h in the presence of the NaOH/hydrogen peroxide system (J. Chem. Soc., Perkin Trans. 1, 1995, 1467-1468).
Despite this improvement, the three-phase method cannot be applied to substrates which are sensitive to hydroxide ions (J. Chem. Soc., Perkin Trans. 1, 1997, 3501-3507). A further disadvantage of these classical conditions is that the polyamino acid forms a gel during the reaction (or even during the preactivation). This restricts the required mixing during the reaction and impedes the working up of the reaction mixture.
Tetrahedron Lett., 2001, 42, 3741-43 discloses that under the three-phase conditions the addition of the phase-transfer catalyst Aliquat(copyright) 336 in the epodixation of phenyl-E-styryl sulfone leads to only a slow reaction rate (reaction time: 4 days) and a poor enantiomeric excess (21% ee). To date, no example of the use of phase-transfer catalysts (PTC) for the epoxidation of xcex1,xcex2-unsaturated enones under the classical three-phase Julixc3xa1-Colonna conditions has been disclosed.
The Julixc3xa1-Colonna epoxidation has been improved further by a change in the reaction procedure. According to Chem. Commun., 1997, 739-740, (pseudo)-anhydrous reaction conditions can be implemented by using THF, 1,2 dimethoxyethane, tert-butyl methyl ether, or ethyl acetate as solvent, a non-nucleophilic base (for example, DBU), and a urea/hydrogen peroxide complex as oxidant. The epoxidation takes place distinctly more quickly under these so-called two-phase reaction conditions. According to J. Chem. Soc., Perkin Trans. 1, 1997, 3501-3507, therefore, the enantioselective epoxidation of hydroxide-sensitive enones under the Julixc3xa1-Colonna conditions is also possible for the first time in this way.
However, the observation that, on use of the two-phase conditions, the polyamino acid must be preactivated in a separate process in order to achieve rapid reaction times and high enantiomeric excesses proves to be a distinct disadvantage. Several days are needed for this preactivation, which takes place by stirring in a toluene/NaOH solution. According to Tetrahedron Lett., 1998, 39, 9297-9300, the required preactivated catalyst is then obtained after a washing and drying procedure. However, the polyamino acid preactivated in this way forms a paste under the two-phase conditions, which impedes mixing during the reaction and the subsequent workup. According to EP-A 1,006,127, this problem can be solved by adsorbing the activated polyamino acid onto a solid support. Polyamino acids on a silica gel support are referred to as SCATs (silica adsorbed catalysts).
A further disadvantage of the two-phase conditions is, however, that the use of costly, non-nucleophilic bases (for example, DBU) is necessary in order to make the reaction possible.
According to EP-A 1,006,111, a further variant of the Julia-Colonna epoxidation is catalysis of the enantioselective epoxidation by the activated polyamino acid in the presence of water, a water-miscible solvent (for example, 1,2-dimethoxyethane), and sodium percarbonate. The use of water-miscible solvents complicates the workup (extraction) in this process.
In the Julixc3xa1-Colonna epoxidation, the reaction rate and the enantiomeric excess (ee) that can be achieved depend greatly on the polyamino acid used and the mode of preparation thereof (Chirality, 1997, 9, 198-202). In order to obtain approximately comparable results, a standard system with poly-L-leucine (pll) as catalyst and trans-chalcone as precursor is used throughout for the development and description of novel methods in the literature. However, besides D- or L-polyleucine, other poly-amino acids such as, for example, D- or L-neopentylglycine are also used successfully (EP-A 1,006,127).
The object of the present invention was to provide a process that makes the polyamino acid-catalyzed enantioselective epoxidation of xcex1,xcex2-unsaturated enones and xcex1,xcex2-unsaturated sulfones possible but is not subject to the disadvantages of the above-described variants of the Julixc3xa1-Colonna epoxidation. It was intended in particular to find a rapid and broadly applicable method that avoids preactivation of the polyamino acid, which must be carried out separately, the use of costly bases and oxidants, and potentially problematic types of reaction procedure and of workup. At the same time, it was intended that the process have advantages in relation to the space/time yield, the handling, economics, and ecology on the industrial scale.
It has now been found, surprisingly, that the epoxidation of xcex1,xcex2-unsaturated enones and xcex1,xcex2-unsaturated sulfones can be carried out with the use of specific phase-transfer catalyst under three-phase conditions with substantially shorter reaction times and, at the same time, even higher enantiomeric excesses.
The invention thus relates to a process for the epoxidation of xcex1,xcex2-unsaturated enones or xcex1,xcex2-unsaturated sulfones in the presence of
(1) a water-soluble base,
(2) an oxidant,
(3) a diastereomer- and enantiomer-enriched homo-polyamino acid as catalyst,
(4) water,
(5) an organic solvent that is immiscible or has only limited miscibility with water, and
(6) a phase-transfer catalyst of the formula (I):
(R1R2R3R4A)+Xxe2x88x92xe2x80x83xe2x80x83(I)
where
A is N or P,
Xxe2x88x92 is an inorganic or organic anion,
R1 and R2 are identical or different and are alkyl, aryl, aralkyl, cycloalkyl, or heteroaryl radicals that are optionally substituted by one or more identical or different halogen radicals, and
R3 and R4 are identical or different and are alkyl, aryl, aralkyl, cycloalkyl, or heteroaryl radicals that are optionally substituted by one or more identical or different halogen radicals or R3 and R4 together form a C4-C6-cycloalkyl ring with A,
where
(i) the total of the carbon atoms and heteroatoms present in the radicals R1, R2, R3, and R4 is at least 13, and
(ii) the accessibility q of the phase-transfer catalyst is in the range 0.6 to 1,3, where q is calculated from the following formula:   q  =      ∑          x      =      1        4  
[1/(total of the carbon atoms and heteroatoms in Rx)]
As an essential feature, the process according to the invention includes the use of specific phase-transfer catalysts.
The variable called the accessibility q is an empirical parameter of a given phase-transfer catalyst of the general formula (I), which has already been described in the literature for tetraalkylammonium salts (ACS Symp. Ser., 1997, 659, 100-102). The phase-transfer catalysts employed in the process according to the invention have an accessibility q in the range 0.6-1.3, preferably in the range 0.7-1.3, and particularly in the range 0.8-1.2.
Xxe2x88x92 in the general formula (I) is preferably Fxe2x88x92, Clxe2x88x92, Brxe2x88x92, Ixe2x88x92, OHxe2x88x92, NO3xe2x88x92, HSO4xe2x88x92, SO4xe2x88x92, CH3COOxe2x88x92, CF3COOxe2x88x92, C2H5COOxe2x88x92, C3H7COOxe2x88x92, CF3SO3xe2x88x92, or C4F9SO3xe2x88x92.
Phase-transfer catalysts of the general formula (I) that have proved suitable are those in which A and Xxe2x88x92 have the above-mentioned meanings, R1, R2, R3, and R4 are identical or different and are C1-C18-alkyl, C6-C18-aryl, C7-C19-aralkyl, C5-C7-cycloalkyl, or C3-C18-heteroaryl and, at the same time, the above-mentioned conditions (i) and (ii) are met.
Particularly suitable phase-transfer catalysts are ((C4H9)4N)+Halxe2x88x92, particularly ((C4H9)4N)+Brxe2x88x92, ((C4H9)4P)+Halxe2x88x92 (particularly ((C4h9)4P)+Brxe2x88x92), or ((C4H9)4N)+HSO4xe2x88x92.
Phase-transfer catalysts such as Aliquat(copyright) 336 ([(CH3)(C8H17)3N+]Clxe2x88x92) and Aliquat(copyright) 175 ([(CH3)(C4H9)3N+]Clxe2x88x92), for which accessibility is outside the range of values 0.6 to 1.3, and phase-transfer catalysts such as PEG 400, by contrast, do not lead to the advantages of the process according to the invention. When such catalysts are used, the target products are obtained with only poor enantiomeric excess or poor space-time yield.
The phase-transfer catalysts to be employed according to the invention are normally commercially available or else can be prepared by methods familiar to those skilled in the art.
The amount of added phase-transfer catalyst is not critical and is normally in the range 0.1 to 20 mol % (preferably in the range 0.5 to 15 mol %, and particularly preferably in the range 0.5 to 11 mol %), in each case based on the xcex1,xcex2-unsaturated enones or xcex1,xcex2-unsaturated sulfone employed. However, it is to be observed with amounts which are even lower than 0.1 mol % that the reaction rate decreases markedly, while the high enantiomeric excess is unchanged.
It is possible to employ as xcex1,xcex2-unsaturated enones or xcex1,xcex2-unsaturated sulfones the compounds of the general formula (II): 
in which
X is (Cxe2x95x90O) or (SO2), and
R5 and R6 are identical or different and are (C1-C18)-alkyl, (C2-C18)-alkenyl, (C2-C18)-alkynyl, (C3-C8)-cycloalkyl, (C6-C18)-aryl, (C7-C19g)-aralkyl, (C1-C18)-heteroaryl, or (C2-C19)-heteroaralkyl, each of which radicals is optionally substituted once or more than once by identical or different radicals R7, halogen, NO2, NR7R8, PO0-3R7R8, SO0-3R7, OR7, CO2R7, CONHR7, or COR7, and
where optionally one or more CH2 groups in R5 and R6 are replaced by O, SO0-2, NR7, or PO0-2R7,
where R7 and R8 are identical or different and are H, (C1-C18)-alkyl, (C2-C18)-alkenyl, (C2-C18)-alkynyl, (C3-C8)-cycloalkyl, (C6-C18)-aryl, (C1-C18)-heteroaryl, (C1-C8)-alkyl-(C6-C8)-aryl, (C1-C8)-alkyl-(C1-C19)-heteroaryl, (C1-C8)-alkyl-(C3-C8)-cycloalkyl, each of which radicals is optionally substituted once or more than once by identical or different halogen radicals.
A (C1-C18)-alkyl radical means for the purpose of the invention a radical that has 1 to 18 saturated C atoms and that may have branches anywhere. It is possible to include in this group in particular the radicals methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
A (C2-C18)-alkenyl radical has the features mentioned for the (C1-C18)-alkyl radical, with the necessity for at least one carbon-carbon double bond to be present within the radical.
A (C2-C18)-alkynyl radical has the features mentioned for the (C1-C18)-alkyl radical, with the necessity for at least one carbon-carbon triple bond to be present within the radical.
A (C3-C8)-cycloalky radical means a cyclic alkly radical having 3 to 8 carbon atoms and, where appropriate, a branch anywhere. Included are, particularly, radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. One or more double bonds may be present in this radical.
A (C6-C18)-aryl radical means an aromatic radical having 6 to 18 carbon atoms. Included are, particularly, radicals such as phenyl, naphthyl, anthryl, and phenanthryl.
A (C7-C19)-aralkyl radical means a (C6-C18)-aryl radical linked via a (C1-C8)-alkyl radical to the molecule.
A (C1-C18)-heteroaryl radical designates for the purpose of the invention a five-, six-, or seven-membered aromatic ring system that has 1 to 18 carbon atoms and that has one or more heteroatoms (preferably N, O, or S) in the ring. These heteroaryl radicals include, for example, 2- and 3-furyl, 1-, 2-, and 3-pyrrolyl, 2- and 3-thienyl, 2-, 3-, and 4-pyridyl, 2-, 3-, 4-, 5-, 6-, and 7-indolyl, 3-, 4-, and 5-pyrazolyl, 2-, 4-, and 5-imidazolyl, 1-, 3-, 4-, and 5-triazolyl, 1-, 4-, and 5-tetrazolyl, acridinyl, quinolinyl, phenanthridinyl, 2-, 4-, 5-, and 6-pyrimidinyl, and 4-, 5-, 6-, and 7-(1-aza)-indolizinyl.
A (C2-C19)-heteroaralkyl radical means a heteroaromatic system corresponding to the (C7-C19)-aralkyl radical.
Halogen or Hal mean in the context of this invention fluorine, chlorine, bromine, and iodine.
The substrates preferably employed in the process according to the invention are preferably xcex1,xcex2-unsaturated enones or xcex1,xcex2-unsaturated sulfones of the general formula (II) in which R5 and R6 are identical or different and are (C1-C12)-alkyl, (C2-C12)-alkenyl, (C2-C12)-alkynyl, (C5-C8)-cycloalkyl, (C6-C12)-aryl, or (C1-C12)-heteroaryl, each of which radicals is optionally substituted once or more than once by identical or different radicals R7, halogen, NO2, NR7R8, PO0-3R7R8, or OR7, and R7 and R8 have the meanings indicated above for the general formula (II).
Substrates particularly preferably employed in the process according to the invention are xcex1,xcex2-unsaturated enones or xcex1,xcex2-unsaturated sulfones of the general formula (II) in which R5 and R6 are identical or different and are (C1-C12)-alkyl, (C2-C12)-alkenyl, (C2-C12)-alkynyl, (C5-C8)-cycloalkyl, (C6-C12)-aryl, or (C1-C12)-heteroaryl, each of which radicals is optionally substituted once or more than once by identical or different radicals R7, halogen, NO2, NR7R8, PO0-3R7R8, or OR7, and R7 and R8 have the meanings indicated above for the general formula (II), with the proviso that at least one of the radicals R5 or R6 is a (C2-C12)-alkenyl, (C2-C12)-alkynyl, (C6-C12)-aryl-, or (C1-C12)-heteroaryl radical.
It is particularly preferred to subject substrates of the general formula (III) to the epoxidation according to the invention: 
where
n and m are identical or different and are the numbers 0, 1, 2, or 3,
R9 and R10 are identical or different and are NR7R8, NO2, OR7, (C1-C12)-alkyl, (C2-C12)-alkenyl, (C2-C12)-alkynyl, (C5-C8)-cycloalkyl, (C6-C12)-aryl, or (C1-C12)-heteroaryl, each of which radicals R9 and R10 is optionally substituted once or more than once by identical or different halogen radicals, and
R7 and R8 have the meanings mentioned previously for formula (II).
The process according to the invention for preparing the enantiomer-enriched epoxides is carried out in the presence of diastereomer- and enantiomer-enriched homo-polyamino acids as catalyst. It is possible in this connection to use a wide variety of diastereomer- and enantiomer-enriched homo-polyamino acids. Preference is given to the use of homo-polyamino acids selected from the group of polyneopentylglycine, polyleucine, polyisoleucine, polyvaline, polyalanine, and polyphenylalanine. The most preferred from this group are polyneopentylglycine and polyleucine.
The chain length of the polyamino acids will normally be chosen in this connection so that, on the one hand, the chiral induction in the reaction is not impaired and, on the other hand, the costs of synthesizing the polyamino acids are not too great. The chain length of the homo-polyamino acids is preferably in the range from 5 to 100 amino acid repeating units, preferably in the range from 7 to 50 amino acid repeating units. Homo-polyamino acids with 10 to 40 amino acids are very particularly preferred.
The homo-polyamino acids to be employed are not subjected before the epoxidation to any separate preactivation with intermediate isolation nor are they applied to an inorganic support. This increases the economic attractiveness of the process considerably and moreover facilitates industrial implementation.
The homo-polyamino acids can be either employed as such unchanged in the reaction or previously crosslinked with polyfunctional amines or chain-extended by other organic polymers. The crosslinking amines advantageously employed for a crosslinking are diaminoalkanes, preferably 1,3-diaminopropane, or crosslinked hydroxy- or aminopolystyrene (CLAMPS, commercially available). Suitable polymer enlargers are preferably nucleophiles based on polyethylene glycol or polystyrene. Polyamino acids modified in this way are described in Chem. Commun., 1998, 1159-1160, and Tetrahedron: Asymmetry, 1997, 8, 3163-3173.
The homo-polyamino acids to be employed in the epoxidation themselves can be prepared by state of the art methods (J. Org. Chem., 1993, 58, 6247-6254, or Chirality, 1997, 9, 198-202). The method is to be applied to both optical antipodes of the amino acids. The use of a particular antipode of a polyamino acid correlates with the stereochemistry of the epoxide, that is to say a poly-L-amino acid leads to the optical antipode of the epoxide that is obtained with a poly-D-amino acid.
The amount of the homo-polyamino acid employed is not critical and is normally in the range 0.0001 to 40 mol % (preferably in the range 0.001 to 20 mol %, particularly preferably in the range 0.01 to 15 mol %, and especially in the range 1 to 15 mol %), in each case based on the xcex1,xcex2-unsaturated enone or xcex1,xcex2-unsaturated sulfone employed.
The oxidants used are, as a rule, peroxides, peracids, or inorganic oxidants such as sodium hypochlorite or sodium percarbonate. Peroxides, peracids, or sodium hypochlorite are preferred. An aqueous H2O2 solution is particularly preferably employed. This aqueous solution may moreover have all the usual concentrations. Further oxidants to be employed in this reaction are the compounds mentioned in Methoden Org. Chem. (Houben-Weyl), volume 4/1a+b, 59-319, and the compounds mentioned in Oxidation in Organic Chemistry, ACS Monograph 186, Washington D.C., 1990, 1-47.
The amount of the oxidant employed may be varied within the wide limits of 1 to 40 equivalents. Surprisingly, and advantageously, the reaction according to the invention still takes place with short reaction times and high enantiomeric excesses even with relatively small amounts of oxidant in the range 1 to 10 equivalents, preferably 1 to 3 equivalents, particularly preferably 1.1 to 2.5 equivalents.
The process according to the invention is carried out in the presence of a water-soluble base. It has proved suitable to employ for this purpose alkali metal hydroxides such as NaOH, KOH, or LiOH. The base is normally employed in the form of an aqueous solution.
The amount of the base employed may be varied within the wide limits of 0.1 to 10 equivalents. Surprisingly, and advantageously, the reaction according to the invention still takes place with short reaction times and high enantiomeric excesses even with relatively small amounts of bases in the range 0.5 to 5 equivalents, preferably 0.8 to 2 equivalents.
The process according to the invention is carried out using a solvent that is immiscible or has only limited miscibility with water. A solvent is regarded as having limited miscibility with water in the context of this invention if a mixture of the organic solvent and water at 20xc2x0 C. can contain no more than 20% by weight (preferably not more than 10% by weight, and particularly not more than 8% by weight) of water in order to remain a single phase.
Suitable organic solvents are in general unsubstituted or substituted aromatic hydrocarbons, aliphatic hydrocarbons, haloalkanes, and ethers. Particularly suitable are toluene, xylene, hexane, tert-butyl methyl ether, diethyl ether, chloroform, and methylene chloride.
In the optimization of the enantiomeric excess and the reaction rate as a function of the solvent used, similar effects are observed as under conventional three-phase conditions. That is to say, high enantiomeric excesses are obtained, particularly in aromatic hydrocarbons such as toluene, whereas particularly short reaction times are achieved in ethers such as tert-butyl methyl ether or in haloalkanes such as chloroform.
It has furthermore been found that the homo-polyamino acid pll aggregates in tert-butyl methyl ether. Hence tert-butyl methyl ether is an interesting and suitable solvent for a continuous reaction procedure.
The temperature used in the epoxidation is generally in the range from xe2x88x9210 to +50xc2x0 C., preferably in the range from 0 to +40xc2x0 C., and particularly at +10 to +30xc2x0 C.
The pH set during the reaction can be chosen so that an excess of deprotonated H2O2 is present compared with nondeprotonated H2O2. On the other hand, the pH in the reaction should not be chosen to be so high as to harm the organic compounds that are employed. The pH is preferably in the range 7 to 14, more preferably in the range 7.5 to 13.
The water content of the system normally results from the fact that, as previously described, individual reaction components of the system, such as the base and the oxidant, are employed in the form of aqueous solutions. The total water content in the reaction mixture is in the range 1 to 70% by weight, preferably in the range 5 to 50% by weight, based on the complete reaction mixture.
In relation to carrying out the reaction, the procedure is normally carried out in such a way that the base, the homo-polyamino acid, the phase-transfer catalyst, the solvent, water, and the substrate are mixed and then the oxidant is added.
The process according to the invention is distinguished by greatly reduced reaction times. Instead of requiring days, epoxidation of the xcex1,xcex2-unsaturated enones and of the xcex1,xcex2-unsaturated sulfones can be achieved with high conversion and high enantioselectivity in only a few hours or even only minutes.
The use according to the invention of the phase-transfer catalyst as cocatalyst permits the necessary amounts of oxidant and of base to be reduced very markedly without having an adverse effect on the reaction rate, conversion, or enantiomeric excess. An additional advantage is that particularly low-cost bases and oxidants can be employed.
Because of the very short reaction times, for the first time hydroxide-sensitive substrates, which cannot be successfully epoxidized by the conventional three-phase conditions (J. Chem. Soc., Perkin Trans. 1, 1997, 3501-3507), are also amenable to enantioselective epoxidation under aqueous, three-phase conditions by the process according to the invention.
The following examples further illustrate details for the process of this invention. The invention, which is set forth in the foregoing disclosure, is not to be limited either in spirit or scope by these examples. Those skilled in the art will readily understand that known variations of the conditions of the following procedures can be used. Unless otherwise noted, all temperatures are degrees Celsius and all percentages are percentages by weight.